This application proposes to investigate abnormalities in human heat shock protein 60 (HSP60) in schizophrenia. This is potentially important as abnormalities of hsp60 in schizophrenia may impair cellular responses to stress; the biological role of normal hsp60 is to protect cells from oxidant injury and other forms of stress. This proposal is based on findings that 27% (16/59) of patients with schizophrenia had high-titer serum IgG antibodies to recombinant human hsp60 compared to 0% (0/81) of disease controls and 3% (2/66) of normal subjects. Also, in cerebrospinal fluid (CSF) anti-hsp60 antibodies were found in 53% (8/15) of patients with schizophrenia compared to 6% of disease controls, and 0% (0/6) normal subjects. Additional data suggests that this aberrant immune response may arise as a result of a genetic alternation of brain hsp60 in schizophrenia; the site of a cDNA sequence abnormalities in brain hsp60 coincides with the location of a 11-me peptide epitope of hsp60 targeted by the anti-hsp 60 antibodies. The specific aims are (1) are anti-hsp60 antibodies present in drug-naive patients with schizophrenia; (2) can serum antibody findings be replicated in a new patient population and are CSF anti-hsp60 antibodies more specifically associated with schizophrenia; (3) Is there a unique clinical profile or specific clinical features associated with anti-hsp60 antibody-positive patients with schizophrenia; (4) what is the molecular basis of the abnormal response to hsp60; and (50 does epitope localization of the anti-hsp60 antibodies correlate with more specific clinical or biological abnormalities in patients with schizophrenia. All antibody testing with be by Western blotting. Antibody-positive and negative patients with schizophrenia will be compared using several clinical measures grouped under three domains: demographic and historical, current clinical symptoms and neuropsychological performance. Molecular studies will involve genomic and cDNA cloning of hsp60 from peripheral and brain tissue. Epitope mapping will be done by ELISA using overlapping peptides spanning the entire normal human hsp60 sequence.